Case
A 9-month-old female presented with hepatosplenomegaly and was found to
have hyperleukocytosis (WBC 1100 k/µL), anemia (2.4 g/dL), and
thrombocytopenia (27 k/µL). Flow cytometry confirmed the diagnosis of
pro-B ALL and cytogenetics revealed a KMT2A rearrangement (4;11
translocation). She was initiated on therapy per Children’s Oncology
Group study AALL15P1 (ClinicalTrials.gov Identifier: NCT02828358,
Interfant-06 backbone10 with addition of azacitidine
blocks). Post-induction minimal residual disease (MRD) analysis was
positive for residual B-ALL (0.73% by flow cytometry; persistent 4;11
translocation by Fluorescence in situ Hybridization [FISH]). She
continued therapy per AALL15P1 protocol with azacitidine block 1,
consolidation, azacitidine block 2, and interim maintenance 1, after
which she had refractory disease with circulating blasts.
Given persistent disease, CD19 CAR-T therapy was the next intended
therapy. T-cells were collected following marrow recovery after interim
maintenance 1. While awaiting ex-vivo CAR-T manufacturing, she received
venetoclax, vincristine, dexamethasone, and
pegaspargase.11 She tolerated this protocol well, only
complicated by neutropenia and pre-septal cellulitis which responded
well to antibiotics. End of course bone marrow evaluation with B-cell
flow-cytometry MRD analysis was negative. However, cytogenetics revealed
persistent KMT2A- r in 14% of cells. Flow cytometric analysis
demonstrated AML with monocytic differentiation, representing 39% of
marrow cells. Given the lack of CD19, Tisagenlecleucel was not infused.
Instead, a myeloid-directed individualized therapy was initiated based
on the VENAML study12, cohort C consisting of
venetoclax, cytarabine, and azacitidine. End of course bone marrow
evaluation was negative for abnormal myeloid blasts but B-ALL MRD show
12.6% abnormal lymphoblasts, indicating a reversion back to a lymphoid
immunophenotype. Given that her disease was positive for CD19 and CD33,
she was initiated on therapy consisting of a combination of blinatumomab
and gemtuzumab13. End of course marrow demonstrated
79% B-cell lymphoblasts that were now CD19 negative by flow cytometry.
She then received another therapeutic approach with myeloid and lymphoid
directed components, including both CPX-351 (liposomal daunorubicin and
cytarabine) and Inotuzumab. Her course was complicated by neutropenia
and Streptococcus mitis bacteremia that did not require intensive care
unit support. At the end of this course, the bone marrow biopsy was
morphologically normal and flow-based MRD testing was negative on both
B-ALL and AML MRD. Furthermore, FISH for KMT2A rearrangement was
negative for the first time during her treatment. Sequencing for
rearrangements of the immunoglobulin receptor (ClonoSeq, Adaptive
Biotechnologies) remained positive for low level residual disease (48
residual clones per million nucleated cells). Her CSF was positive for
blasts, but cleared with additional intrathecal cytarabine,
hydrocortisone, and methotrexate while preparing for transplant.
She then proceeded to an unrelated umbilical cord transplant.
Post-transplant course was complicated by sinusoidal obstruction
syndrome (SOS), thrombotic microangiopathy (TMA), and multifocal
pneumonia resulting in ARDS requiring ECMO support. Her leukemia
relapsed on day +37 from transplant, with a conversion back to a myeloid
immunophenotype. Cytogenetics redemonstrated her KMT2Arearrangement. Ultimately, she died on post-transplant day +57 from
multi-organ failure.